Nitric oxide, an endothelium-derived relaxing factor, has been implicated in septic shock hypotension. Approximately 50 percent of patients dying of septic shock succumb to refractory hypotension. This study looks at the therapeutic value of nitric oxide synthase (NOS) inhibition in an awake canine model of septic shock by serially studying cardiopulmonary function, laboratory parameters, and survival. Initial experiments in endotoxin-challenged canines with two different NOS inhibitors, Nw-amino-Larginine (Cobb P. et.al., j Exp Med, 1992, v. 176:1175-1189) and Nw-methyl-L-arginine (Cobb P. et.al., Am J Physiol, 1995, v.268:H1634-H1642), have revealed unexpected toxicities and some limitations to this approach. Clinical development of Nw-amino-L-arginine was stopped because of these findings. Nw-methyl-L-arginine is currently in Phase II clinical trials in combination with conventional vasopressors.In our next investigation in this series, lower doses of Nw-methyl-L- arginine were used with and without a conventional vasopressor (epinephrine) to better simulate the clinical conditions under which these agents are likely to be used. This study employed an Escherichia coli peritonitis model to examine the effects of these agents in actual infections. Although it had been hypothesized that these two agents might act synergistically through reversal of sepsis-induced catecholamine hyporesponsiveness, Nw-methyl-L- arginine produced mainly additive effects with epinephrine and could not be shown to improve survival. However, at the doses studied, the combined Nw-methyl-L-arginine and epinephrine were not harmful, and the NOS inhibitor preserved cardiac function better than epinephrine. Thus, although the therapeutic role of NOS inhibition in septic shock remains to be defined, these agents have unique characteristics that may be clinically useful. NOS inhibitors that are highly selective for the induced isoform of this enzyme are being sought for future studies. In addition, we plan to investigate the cardiovascular effects and impact on survival of further up-regulating the nitric oxide pathway in septic shock in the presence and absence of antioxidant therapy.